FDA Gives Direction for BLA Resubmission of Denileukin Diftitox in CTCL

• The FDA has addressed the complete response letter (CRL) requiring Citius Pharmaceuticals, Inc., to incorporate enhanced product testing for denileukin diftitox (Lymphir).¹

• Under their guidance, the company has been given the necessary actions needed to support the resubmission of the biologics license application (BLA) for the agent in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL).

• The resubmission is expected in early 2024.

The FDA has provided additional guidance for the planned resubmission of the BLA for denileukin diftitox for the treatment of patients with relapsed or refractory CTCL after at least 1 prior systemic therapy.¹

According to a press release by Citius Pharmaceuticals, Inc., the FDA has agreed with plans to address the requirements outlined in the CRL received for the agent on July 28, 2023. No clinical safety or efficacy issues were raised with the product or the proposed prescribing information.

Under the CRL the FDA has required Citius to incorporate enhanced product testing and additional controls agreed to with the FDA during the market application review.² With this guidance, a clear path and necessary actions have been provided to support the resubmission of the BLA for denileukin diftitox.¹

Further, the FDA did not request any additional clinical efficacy or safety trials for the resubmission.

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"We are encouraged by the constructive engagement with the FDA," stated Leonard Mazur, chairman and chief executive officer of Citius, in the press release. "Based on the clear feedback from the FDA, Citius plans to complete the CRL remediation activities by the end of the year and file the resubmission in early 2024. We do not expect these efforts will impact our cash runway."

Denileukin diftitox is an engineered recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments. By specifically binding to IL-2 receptors on the cell surface, diphtheria toxin fragments in cells are caused to inhibit protein synthesis.

Previously in 2011 and 2013, orphan drug designations were granted to denileukin diftitox by the FDA for the treatment of peripheral T-cell lymphoma (PTCL) and CTCL, respectively. Then in 2021, denileukin diftitox was granted regulatory approval in Japan for the treatment of CTCL and PTCL, and an exclusive license with rights to develop and commercialize the agent was acquired by the company in all markets except for Japan and certain parts of Asia.

Two investigator-initiated trials evaluating the potential safety and efficacy of denileukin diftitox.³ The first study is in combination with pembrolizumab (Keytruda) for the treatment of patients with recurrent or metastatic solid tumors (NCT05200559), and the other is assessing denileukin diftitox given prior to lymphodepletion chemotherapy and chimeric antigen receptor T-cell therapies for the treatment of patients with relapsed/refractory B-cell lymphomas who are at a high risk for failure from tisagenlecleucel (Kymriah) alone (NCT04855253).^3,4

Data from these trials will help determine whether or not denileukin diftitox should gain regulatory approval in this space. Resubmission of the BLA for denileukin diftitox is planned for early 2024.¹

_REFERENCES:

_{1. Citius Pharmaceuticals, Inc. receives regulatory guidance from the U.S. Food and Drug Administration (FDA) regarding the planned resubmission of the BLA for LYMPHIR™. News release. Citius Pharmaceuticals, Inc. September 8, 2023. Accessed September 8, 2023. https://tinyurl.com/5n8y9nj3}

_{2. Citius Pharmaceuticals, Inc. receives a complete response letter from the U.S. Food and Drug Administration (FDA) for Lymphir™ (denileukin diftitox) for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. July 29, 2023. Accessed September 8, 2023. https://tinyurl.com/54nsnu5k}

_{3. T-regulatory cell depletion with E7777 combined with pembrolizumab in recurrent or metastatic solid tumors. ClinicalTrials.gov. Updated October 5, 2022. Accessed September 8, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05200559}

_{4. Study of E7777 prior to kymriah for R/R DLBCL. ClinicalTrials.gov. Updated July 7, 2023. Accessed September 8, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04855253}